Molecular pathways regulating mitotic spindle orientation in animal cells

Abstract

Orientation of the cell division axis is essential for the correct development and maintenance of tissue morphology, both for symmetric cell divisions and for the asymmetric distribution of fate determinants during, for example, stem cell divisions. Oriented cell division depends on the positioning of the mitotic spindle relative to an axis of polarity. Recent studies have illuminated an expanding list of spindle orientation regulators, and a molecular model for how cells couple cortical polarity with spindle positioning has begun to emerge. Here, we review both the wellestablished spindle orientation pathways and recently identified regulators, focusing on how communication between the cell cortex and the spindle is achieved, to provide a contemporary view of how positioning of the mitotic spindle occurs.Key words: Spindle, Microtubules, Oriented cell division, Polarity, Mitosis, Centrosome IntroductionAll multicellular animals are tasked with two fundamental developmental challenges: generating cellular diversity and forming three-dimensional tissues, both of which initiate from a singlecelled zygote. Cellular diversity is spawned by cell divisions yielding non-identical daughters, and tissue morphogenesis is established through the precise three-dimensional arrangement of cell divisions that form the overall architecture of the organism. Both of these essential challenges are resolved in part through oriented cell division, which regulates embryogenesis, organogenesis and cellular differentiation. Notably, oriented cell divisions, and hence asymmetric cell divisions, remain crucial throughout adulthood as well, functioning as the basis for tissue homeostasis during growth and wound repair. One primary feature of oriented cell division is the proper positioning of the mitotic spindle relative to a defined polarity axis. In principle, spindle orientation is achieved through signaling pathways that provide a molecular link between the cell cortex and spindle microtubules. These pathways are thought to elicit both static connections and dynamic forces on the spindle to achieve the desired orientation prior to cell division. Although our knowledge of the signaling molecules involved in this process and our understanding of how they each function at the molecular level remain limited, collective efforts over the years have shed light on the importance of spindle orientation to animal development and function. Moreover, emerging evidence shows an association between improper spindle orientation and a number of developmental diseases as well as tumor formation. The study of spindle orientation is therefore fundamental to both developmental biology and human disease.Over a century ago, Oscar Hertwig discovered that sea urchin embryos biased the orientation of the mitotic spindle along their long axis, which led to a model (the 'Hertwig Rule') in which cells orient divisions in response to mechanical forces (Hertwig, 1884). The Hertwig model stated that mechanical regulation was the primary determinant of spindle orien...

FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis

“…Although significant progress has been made towards understanding how cells couple cortical polarity signals and spindle positioning, how cells receive external stimuli and how these are translated at the cortex are poorly understood 3 . During early embryonic development, mechanical forces are believed to play a critical role in morphogenesis in part through control of cell division orientation 60 .…”

“…D efective spindle orientation is associated with developmental abnormalities often associated with severe diseases, including neurological disorders, polycystic kidneys and tumorigenesis [1][2][3] . Cortical pulling forces generated by dynein on astral microtubules define the position and orientation of the spindle.…”

“…Fink et al 7 , elegantly showed that external forces transmitted through the retraction fibres (RFs) can guide mitotic spindle orientation in adherent cells, whereas external forces have also been shown to control spindle orientation in vivo in the zebrafish EVL 8 . Despite an abundance of molecules identified as regulators of mitotic spindle positioning and orientation, including microtubule-and actin-associated proteins, kinases, cell polarity proteins, adherens junction proteins, transmembrane receptors and phosphoinositides 3,5,[7][8][9][10][11][12][13][14][15] , how are external forces transmitted to the cell cortex and bias cortical cues is still poorly understood.…”

Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis

“…Up to now, the intrinsic molecular machinery positioning the mitotic spindle and its coupling to intrinsic cell polarities retained much attention [2][3][4] . Astral microtubules play a key role in division orientation by linking the mitotic spindle to the cell cortex and transmitting pulling forces to trigger the spindle motion.…”

Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

“…The molecular asymmetries guide directional exocytosis and secretion of digestive enzymes from pancreas, milk from mammary epithelium and vectorial transfer of nutrients across the gut epithelium to blood [1]. Furthermore, extension of epithelial monolayers requires that cell divisions occur in the plane of the sheet and many key cell polarity proteins are involved in determining alignment of the mitotic spindle so that it is perpendicular to the axis of apico-basal polarity [4][5][6]. In addition to many proteins, lipids are also asymmetrically distributed in polarized cells [1].…”